Tissue engineering and cell therapy is a new and exciting approach to the treatment of acute and chronic diseases. The potential success of this therapeutic approach lies in the growing appreciation that most disease processes are not due to the lack of a single protein but develop due to alterations in complex interactions of a variety of cell products. Cell therapy is dependent on cell and tissue culture methodologies to expand specific cells to replace important differentiated processes deranged or lost in various disease states. The systemic inflammatory response syndrome, or SIRS, is a catastrophic sequela of a variety of clinical insults, including infection, pancreatitis, and cardiopulmonary bypass, and claims over forty thousand lives in the U.S. each year. The exceptionally high mortality associated with the syndrome is due in part to the development of the highly lethal multiple system organ failure syndrome (MOF) in a subset of patients with SIRS. The sequential failure of organ systems apparently unrelated to the site of the initial insult has been correlated with altered plasma cytokine levels observed in sepsis. The data accrued in this Phase II proposal will develop a miniature cellular device which will be accessed via an extracorporeal catheter system. This extracorporeal device, named bioartificial renal epithelial cell system (BRECS), will be developed and tested for efficacy in treating SIRS and sepsis in a pre-clinical large animal model of septic shock. At the end of Phase II, the developed pre-clinical data will be used for an IND application for the clinical testing of this therapeutic cellular device in treatment of septic shock and SIRS. Relevance: The goal of this proposal is to develop a cell based therapy that can be used to reverse the serious clinical events associated with patients who develop septic shock. The success of this project would decrease the very high mortality rate of septic shock and therefore contribute to patient recovery from this devastating disease process. PUBLIC HEALTH RELEVANCE The long-term goal of this proposal is to develop a bioartificial renal epithelial cell system (BRECS) that effectively adds therapeutic value to a variety of disease processes. The target application is in the treatment of Systemic Inflammatory Response Syndrome (SIRS) and sepsis. Severe sepsis with SIRS occurs in 200,000 patients annually in the U.S. and has a mortality rate of 30 40%, even with use of intensive care units and broad spectrum antibiotics. This device would greatly reduce the multiorgan effects of sepsis and SIRS, thus improving the clinical outcome of patients affected by these disease processes. [unreadable] [unreadable] [unreadable]